The RhoGEF GEF-H1 is required for RAS oncogene-driven Pancreatic cancer

3^rd World Congress on Cancer Science & Therapy

October 21-23, 2013 DoubleTree by Hilton Hotel San Francisco Airport, CA, USA

Robert Rottapel, Jane Cullis David Meiri, Nikolina Radulovich, Jose Larose, Mauricio Medrano, Richard Marcotte, Chris Marshal, Jason Moffat, Ben Neel, Anne-Claude Gingras3 and Ming-Sound Tsao

ScientificTracks: J Cancer Sci Ther

Abstract :

Activating mutations in RAS are a nearly uniform genetic feature of pancreatic adenocarcinomas. Cellular transformation by oncogenic RAS engages the MAPK pathway under strict spatiotemporal regulation by the scaffold protein KSR-1. In order to gain insight into the signaling elements required for RAS transformation we performed a high content shRNA based genetic screen on human cancer cell lines harboring RAS mutations. We describe the identification of GEF-H1, a RHO guanine nucleotide exchange factor known to be associated with the microtubule-array required for RAS transformation. We show that GEF-H1 is essential for the growth and survival of RAS V12 -transformed cancer cells and for tumor growth in in vivo pancreatic xenograft models. GEF-H1 expression is induced by oncogenic RAS and is correlated with pancreatic neoplastic progression in patient tumor samples. We provide mechanistic insight into a novel function for GEF-H1 as an activator of the MAPK pathway: GEF-H1 is required to recruit PP2A B? subunits to its substrate KSR-1 which when dephosphorylated on S392 potentiates flux through the MAPK pathway. Our results therefore identify GEF-H1 as an amplifier of MAPK signaling and provide mechanistic insight to the progression of RAS-mutated cancers.